Xiaoliang Wang

Long-term treatment of l-3-n-butylphthalide attenuated neurodegenerative changes in aged rats.

It is shown that l-3-n-butylphthalide (l-NBP), the isomer of dl-NBP (racemic 3-n-butylphthalide, a new anti-cerebral ischemic agent) significantly attenuated cerebral hypoperfusion-induced learning dysfunction and brain damage in rats. In the present study, l-NBP (10 and 30xa0mg/kg) long-term (3-month) treatment of aged rat (21-month-old) significantly improved the learning and memory capability measured by the Morris water maze test. Hematoxylin–eosin-stained slices showed that both l-NBP at 30xa0mg/kg, and memantine as control at 20xa0mg/kg, attenuated the neurodegenerative changes in aged rats. l-NBP treatment significantly increased the choline acetyltransferase activity and dose-dependently decreased the acetylcholinesterases activity in the hippocampus of aged rats. The immunohistological study demonstrated that expressions of β-secretase and hyperphosphorylated tau protein were significantly increased in the hippocampus CA1 subfield and parietal cortex in aged rats. However, they were decreased significantly by treatment of l-NBP and memantine for 3xa0months. Our results indicated that long-term treatment with l-NBP might prevent age-related neurodegenerative changes by modulation of cholinergic system, reduction of phosphorylated tau and maintain structure and morphology of neurons. Therefore, l-NBP might be a potential drug for treatment of senile dementia.

l-3-n-Butylphthalide attenuates β-amyloid-induced toxicity in neuroblastoma SH-SY5Y cells through regulating mitochondrion-mediated apoptosis and MAPK signaling.

Alzheimers disease (AD) is a progressive neurodegenerative disease. Amyloid-β protein (Aβ), the hallmark of AD, invokes a cascade of mitochondrial dysfunction and eventually leads to neuronal death. l-3-n-Butylphthalide (l-NBP) has shown the potent neuroprotective effects in stroke and AD animal models. The present study is to evaluate the neuroprotective effect of l-NBP on Aβ25–35-induced neuronal injury and the possible mechanism in the human neuroblastoma SH-SY5Y cells. Our results showed that l-NBP significantly attenuated Aβ25–35-induced cell death and reduced neuronal apoptosis. l-NBP significantly inhibited Aβ25–35-induced mitochondrial dysfunction, including mitochondrial membrane potential reduction, and reactive oxygen species production. Furthermore, l-NBP could partially reverse the elevations of Aβ25–35-induced active caspase-3, caspase-9, and cytochrome c expressions, and the downregulation of anti-apoptosis protein Bcl-2. Moreover, l-NBP markedly inhibited the activations of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase/stress-activated protein kinase signaling pathway. These results demonstrated that l-NBP was capable of protecting neuronal cells from Aβ25–35-induced toxicity through a mitochondrial-dependent apoptotic pathway. Thus, l-NBP shows promising candidate of multi-target neuronal protective agent for the treatment of AD.

Striatal 19S Rpt6 deficit is related to α-synuclein accumulation in MPTP-treated mice

Striatal mitochondrial proteins were investigated using proteomics in the 1-methyl 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinsons disease. Four proteins, 19S proteasome ATPase Rpt6 (19S Rpt6), Lectin-related nature killer cell receptor LY 49S, Zinc finger A20 domain containing 1, and the sodium channel-associated protein 1 isoform 2, were significantly decreased while alpha-synuclein was increased in MPTP-treated mice. The altered levels of 19S Rpt6 and alpha-synuclein were further verified by Western blot. Experiments using small interfering RNA (siRNA) showed that alpha-synuclein was increased by 50% in cultured striatal neurons when 19S Rpt6 was knocked down. Taken together, our results imply that a deficiency in 19S Rpt6 may be partially related to the MPTP-induced increase in alpha-synuclein in the striatum.

Potassium 2-(l-hydroxypentyl)-benzoate attenuates neuroinflammatory responses and upregulates heme oxygenase-1 in systemic lipopolysaccharide-induced inflammation in mice

A neuroinflammatory response is commonly involved in the progression of many neurodegenerative diseases. Potassium 2-(1-hydroxypentyl)-benzoate (PHPB), a novel neuroprotective compound, has shown promising effects in the treatment of ischemic stroke and Alzheimer׳s disease (AD). In the present study, the anti-inflammatory effects of PHPB were investigated in the plasma and brain of C57BL/6 mice administered a single intraperitoneal (i.p.) injection of lipopolysaccharide (LPS). Levels of iNOS and the cytokines TNFα, IL-1β and IL-10 were elevated in plasma, cerebral cortex and hippocampus after LPS injection and the number of microglia and astrocytes in cortex and hippocampus were increased. LPS also upregulated the expression of heme oxygenase-1 (HO-1) in the cortex and hippocampus. PHPB reduced the levels of iNOS and cytokines in the plasma and brain, decreased the number of microglia and astrocytes and further enhanced the upregulation of HO-1. In addition, PHPB inhibited the LPS-induced phosphorylation of ERK, P38 and JNK. These results suggest that PHPB is a potential candidate in the treatment of neurodegenerative diseases through inhibiting neuroinflammation.

Glomexanthones A–C, three xanthonolignoid C-glycosides from Polygala glomerata Lour

Three novel xanthonolignoid C-glycosides, glomexanthones A-C, with a trans-dihydrobenzofuran on B ring and a 2-hydroxymethyl-5-hydroxyl-2-pentenoic acid moiety in the sugar chain were isolated from an ethanol extract of Polygala glomerata. Their structures and absolute configurations were characterized by extensive NMR, MS, and CD spectroscopic studies. Screening results indicated that compounds 1-3 showed moderate neuroprotective effects on L-Glutamic acid-induced cellular damage in human neuroblastoma SK-N-SH cells.

L-3-n-Butylphthalide Regulates Proliferation, Migration, and Differentiation of Neural Stem Cell In Vitro and Promotes Neurogenesis in APP/PS1 Mouse Model by Regulating BDNF/TrkB/CREB/Akt Pathway

Alzheimer’s disease (AD) is characterized by extracellular accumulation of β-amyloid peptides (Aβ) and intracellular neurofibrillary tangles, along with cognitive decline and neurodegeneration. The cognitive deficit is considered to be due to the dysfunction of hippocampal neurogenesis. Although L-3-n-butylphthalide (L-NBP) has been shown beneficial effects in multiple AD animal models, the underlying molecular mechanisms are still elusive. In this study, we investigated the effects of L-NBP on neurogenesis both in vitro and in vivo. L-NBP promoted proliferation and migration of neural stem cells and induced neuronal differentiation in vitro. In APP/PS1 mice, L-NBP induced neurogenesis in the dentate gyrus and improved cognitive functions. In addition, L-NBP significantly increased the expressions of BDNF and NGF, tyrosine phosphorylation of its cognate receptor, and phosphorylation of Akt as well as CREB at Ser133 in the hippocampus of APP/PS1 mice. These results indicated that L-NBP might stimulate the proliferation, migration, and differentiation of hippocampal neural stem cells and reversed cognitive deficits in APP/PS1 mice. BDNF/TrkB/CREB/Akt signaling pathway might be involved.

From stroke to neurodegenerative diseases: The multi-target neuroprotective effects of 3-n-butylphthalide and its derivatives

ABSTRACT Discovering effective agents to slow or stop neurodegeneration is a challenging task. Over decades, only a few drugs were approved by Food and Drug Administration (FDA) and most ended in failure. The lessons learned have switched the strategy of drug discovery from designing highly selective ligands to a network pharmacology approach. This enables many natural products like butylphthalide (NBP) once again to be regarded as a valuable source of leads for drug discovery. In this review, we first start with the neuroprotective effects of NBPs on acute ischemic stroke, and later spread to their applications in major neurodegenerative diseases. The underlying mechanisms are also discussed in order to provide a direction for further study. Hopefully, this review could bring some new insights for drug development in this struggling field.

Protective Effects of L-3-n-Butylphthalide Against H2O2-Induced Injury in Neural Stem Cells by Activation of PI3K/Akt and Mash1 Pathway

It has been reported that oxidative stress could result in damage to the developing brain. L-3-n-butylphthalide (L-NBP) could inhibit neuronal cell apoptosis and has neurogenesis effect in different animal and cellular models. However, whether L-NBP could protect the process of neurogenesis in neural stem cells (NSCs) against oxidative stress injury is still unclear. Here, in the present study, we evaluated the neuroprotective effect of L-NBP in NSCs against H2O2-induced injury and the possible mechanisms. The results showed that L-NBP elevated the proliferation of NSCs by upregulating cyclin D1, and PI3K/Akt might be a possible target in this process. Subsequently, L-NBP was found to promote the migration of NSCs and N-cadherin might be involved in. NSC differentiation was measured using immunofluorescence staining and the results demonstrated that L-NBP could promote the NSCs to differentiate more into neurons. The elevation of achaete-scute homolog1 (Mash1) expression might be a key factor as attenuation of endogenous Mash1 expression by short-interfering RNA could block L-NBP-promoted neuronal differentiation. In summary, L-NBP exerts protective effects in NSCs against H2O2-induced injury by promoting the proliferation, migration and neural differentiation of NSCs, indicating that L-NBP might be a potential therapeutic agent for the neurogenesis-based treatment for some brain diseases, such as Alzheimers disease (AD).

Dl-3-n-Butylphthalide (NBP): A Promising Therapeutic Agent for Ischemic Stroke

BACKGROUND AND OBJECTIVEnStroke is a leading cause of morbidity and mortality in both developed and developing countries all over the world. The only drug for ischemic stroke approved by FDA is recombinant tissue plasminogen activator (rtPA). However, only 2-5% stroke patients receive rtPAs treatment due to its strict therapeutic time window. As ischemic stroke is a complex disease involving multiple mechanisms, medications with multi-targets may be more powerful compared with single-target drugs. Dl-3-n-Butylphthalide (NBP) is a synthetic compound based on l-3-n- Butylphthalide that is isolated from seeds of Apium graveolens. The racemic 3-n-butylphthalide (dl- NBP) was approved by Food and Drug Administration of China for the treatment of ischemic stroke in 2002. A number of clinical studies indicated that NBP not only improved the symptoms of ischemic stroke, but also contributed to the long-term recovery. The potential mechanisms of NBP for ischemic stroke treatment may target different pathophysiological processes, including anti-oxidant, antiinflammation, anti-apoptosis, anti-thrombosis, and protection of mitochondria et al. Conclusion: In this review, we have summarized the research progress of NBP for the treatment of ischemic stroke during the past two decades.